The purpose of this study was to assess the effect of strict avoidance of hypoglycemia on beta-adrenergic sensitivity in a type 1 diabetic patient with hypoglycemia unawareness and a diabetes duration of 55 yr. beta-Adrenergic sensitivity was determined by an isoproterenol test and was expressed as the lowest dose of isoproterenol that increases the heart rate by 25 beats/min (IC25). Plasma epinephrine and symptom responses to hypoglycemia were determined during a 3-h hypoglycemic (3 mmol/L) clamp. Initially, the patient had a near-normal counterregulatory plasma epinephrine response to hypoglycemia but reduced beta-adrenergic sensitivity (IC25, 2 microg) compared to 10 hypoglycemia aware, type 1 diabetic patients (0.65 +/- 0.14 microg) and 10 normal control subjects (1.13 +/- 0.21 microg). After 1 yr of strict avoidance of blood glucose levels below 4 mmol/L, the IC25 decreased to 0.25 microg, reflecting improved beta-adrenergic sensitivity. In conclusion, the reduced beta-adrenergic sensitivity in this patient was probably the reason for hypoglycemia unawareness and was reversed by strict avoidance of hypoglycemia.